Propynyl or dienyl biaromatic compounds

Abstract

The invention relates to novel propynyl or dienyl biaromatic compounds which have the general formula (I)as well as to the use of these compounds in pharmaceutical compositions intended for use in human or veterinary medicine (dermatological, rheumatic, respiratory, cardiovascular and ophthalmological complaints in particular), or alternatively in cosmetic compositions.

What is claimed is:  
     
       1. A propynyl biaromatic compound, having the general formula (I) below:                    
       in which: 
       R 1  is  
       (i) the —CH 3  radical  
       (ii) the radical —CH 2 —O—R 6    
       (iii) the radical —O—R 6 , or  
       (iv) the radical —CO—R 7    
       R 6  and R 7  having the meanings given below,  
       Ar is a radical selected from the group consisting of (a)-(e) below:                    
        R 5  and R 6  have the meanings given below,  
       X is a radical of formula:                    
        R 8  and R 9  have the meanings given below,  
       R 2  and R 3 , which may be identical or different, are selected from the following:  
       (i) a hydrogen atom,  
       (ii) a linear or branched alkyl radical having from 1 to 20 carbon atoms,  
       (iii) a radical —OR 6 ,  
       (iv) a radical —SR 6 ,  
       R 6  is defined below,  
       wherein R 2  and R 3 , taken together, may form, with the adjacent aromatic ring, a 5- or 6-membered ring optionally substituted with methyl groups and/or optionally interrupted by an oxygen or sulfur atom,  
       wherein R 2  and R 3  cannot simultaneously have the meanings (i), (iii) and (iv) mentioned above,  
       R 4  and R 5 , which may be identical or different, are hydrogen atom, a halogen atom, a linear or a branched alkyl radical having from 1 to 20 carbon atoms or a radical —OR 6 ,  
       wherein if R 4  is a hydroxyl radical, then R 2  and R 3  form, with the adjacent aromatic ring, a 5- or 6-membered ring which optionally is substituted with methyl groups and/or optionally interrupted by an oxygen or a sulfur atom,  
       R 6  is a hydrogen atom, a lower alkyl radical or a radical —COR 10    
       R 10  is defined below,  
       R 7  is selected from the following:  
       (a) a hydrogen atom  
       (b) a lower alkyl radical  
       (c) a radical of formula:                    
        wherein R′ and R″ are defined below,  
       (d) a radical —OR 11 ,  
       (e) a radical —NHOR 6 ,  
       R 11  is defined below,  
       R 8  and R 9 , if considered separately, are the same and are either a hydrogen atom or a radical —OR 10 , or R 8  and R 9  are different, and one of them is a hydrogen atom and the other is a lower alkyl radical, or, R 8  and R 9  together form a ring —Y—(CH 2 ) n —Y—, with Y representing an oxygen or a sulfur atom and with n equal to 2 or 3,  
       R 10  is a lower alkyl radical,  
       R 11  is a hydrogen atom, a linear or branched alkyl radical having from 1 to 20 carbon atoms, an alkenyl radical, a mono- or polyhydroxyalkyl radical, an optionally substituted aryl or aralkyl radical, a sugar residue or an amino acid or peptide residue,  
       R′ and R″, which may be identical or different, are selected from a hydrogen atom, a lower alkyl radical, a mono- or polyhydroxyalkyl radical, an optionally substituted aryl radical or an amino acid or sugar residue, or alternatively, taken together, form a heterocycle, or a salt or optical or geometric isomer of said compound.  
     
     
       2. A compound having the general formula (II) below:                    
       in which R 1  and Ar are defined according to claim  1  and wherein R′ 2  and R′ 4 , which may be identical or different, are each a linear or branched alkyl radical having from 1 to 20 carbon atoms. 
     
     
       3. A compound according to claim  1 , wherein said compound is selected from the group consisting of alkali metal, alkaline earth metal, zinc, and organic amine salts. 
     
     
       4. A compound according to claim  1 , which is selected from the group consisting of: 
       4-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-propynyl]benzoic acid,  
       2-hydroxy-4-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-propynyl]benzoic acid,  
       4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid,  
       methyl 2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate,  
       2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid,  
       2-hydroxy-4-[3-(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid,  
       2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzenemethanol,  
       diethanolamine 2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate,  
       lithium 2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate,  
       4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-propynyl]benzoic acid,  
       2-hydroxy-4-[3-(4,4-dimethylthiochroman-6-yl)-1-propynyl]benzoic acid,  
       2-hydroxy-4-[3-(8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoic acid,  
       2-hydroxy-4-[3-(5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoic acid,  
       ethyl 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate,  
       4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide,  
       N-ethyl-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide,  
       4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid morpholide,  
       N-(4-hydroxyphenyl)-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide,  
       4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzaldehyde,  
       4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]phenol,  
       [3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzenemethanol,  
       4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]toluene,  
       hexyl 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate,  
       N-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide,  
       N-hydroxy-2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide,  
       2-methyl-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid,  
       3-methyl-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid,  
       6-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)propa-1,2-dienyl]nicotinic acid,  
       4-[3-(5,5,8,8-tetra-methyl-5,6,7,8-tetrahydro-2-naphthyl)propa-1,2-dienyl]benzoic acid,  
       2-hydroxy-4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)propa-1,2-dienyl]benzoic acid,  
       2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-butynyl]benzoic acid,  
       5-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]-2-pyridinecarboxylic acid,  
       4-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoic acid,  
       2-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]-4-thiophenecarboxylic acid,  
       2-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]-4-thiophenecarboxylic acid,  
       2-hydroxy-4-[3-(3-tert-butyl-4-methoxyphenyl)-1-propynyl]benzoic acid,  
       2-hydroxy-4-[3-(3-tert-butyl-4-hydroxyphenyl)-1-propynyl]benzoic acid.  
     
     
       5. A compound according to claim  3 , selected from the group consisting of: 
       4-[3-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-1-ylidene)-1-propynyl]benzoic acid, and  
       2-hydroxy-4-[3-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-1-ylidene)-1-propynyl]benzoic acid.  
     
     
       6. A compound according to claim  1 , which has at least one of the following characteristics: 
       R 1  represents the radical —CO—R 7 ,  
       Ar represents the radicals of formula (a) or (e).  
     
     
       7. A compound according to one of claim  1 , in which R 8  and R 9  are both hydrogen atoms or one of them represents a hydrogen atom and the other represents a lower alkyl radical. 
     
     
       8. A method of therapy comprising administration of a therapeutically effective amount of at least one compound of formula (I) or (II) according to claim  1 . 
     
     
       9. A method for therapy which involves the administration of a therapeutically effective amount of a compound according to claim  1 , wherein the condition treated is selected from the group consisting of dermatological conditions, inflammatory conditions, opthamological disorders, cancerous or precancerous conditions, alopecia, cardiovascular conditions, and insulin-dependent diabetes. 
     
     
       10. The method of claim  9 , wherein said dermatological condition is selected from the group consisting of: 
       (i) conditions associated with keratinization, which optionally are associated with differentiation and/or proliferation;  
       (ii) keratinization disorders having an immunological and/or immunoallergic component;  
       (iii) dermal and epidermal proliferations, benign or malignant, which are of viral or non-viral origin;  
       (iv) bullosis or collagen disorders;  
       (v) chronological or UV-induced aging of the skin;  
       (vi) actinic keratoses and pigmentation;  
       (vii) stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids;  
       (viii) cutaneous atrophy;  
       (ix) cicatrization disorders;  
       (x) vibices;  
       (xi) promotion of cicatrization;  
       (xii) disorders of sebaceous function;  
       (xiii) general skin complaints of oral origin;  
       (xiv) immunological dermatological conditions; and  
       (xv) skin disorders associated with UV radiation exposure.  
     
     
       11. The method of claim  9 , wherein said disorder is selected from the group consisting of common acne, comedones, polymorphonuclear leukocytes, acne rosacea, nodulocystic acne, acne conglobata, senile acne, solar, medication-related acne, occupational acne, ichthyosis, ichthyosiform states, Darier's disease, palmoplantar keratoderma, leucoplasias and leucoplasiform states, cutaneous or mucous (buccal) lichen; psoriasis, cutaneous, mucous or ungual psoriasis, psoriatic rheumatism, eczema, respiratory atopy, gingival hypertrophy, common warts, flat warts, verruciform epidermodysplasia, oral or florid papillomatoses, proliferations induced by ultraviolet radiation, basocellular or spinocellular epithelioma; corneopathies, promyelocytic leukemia, arthritis, arteriosclerosis, and hypertension. 
     
     
       12. A pharmaceutical composition containing a therapeutically effective amount of a compound according to claim  1 . 
     
     
       13. A composition according to claim  12 , wherein the concentration of said compound is between 0.001% and 5% by weight relative to the composition as a whole. 
     
     
       14. A cosmetic composition which comprises, in a cosmetically acceptable carrier or excipient, a cosmetically effective amount of at least one of the compounds as defined in claim  1 . 
     
     
       15. A cosmetic composition according to claim  14 , wherein the concentration of said compound is between 0.001% and 3% by weight relative to the composition as a whole. 
     
     
       16. A method of hygiene comprising administering an effective amount of a cosmetic composition as defined in claim  14 , for body or hair hygiene. 
     
     
       17. A compound according to claim  2 , which is an alkali metal, alkaline earth metal, zinc, or organic amine salt. 
     
     
       18. A compound according to claim  2 , wherein at least one of the following is satisfied: 
       R 1  is —CO—R 7 , and  
       Ar is a radical of formula (a) or (e).  
     
     
       19. A medicinal composition containing a medicinally effective amount of at least one compound having formula (II) according to claim  2 . 
     
     
       20. A method of therapy which involves the administration of a therapeutically effective amount of a compound according to claim  2 , wherein the condition treated is selected from the group consisting of dermatological conditions, inflammatory conditions, opthamological disorders, cancerous or precancerous conditions, alopecia, cardiovascular conditions, and insulin-dependent diabetes. 
     
     
       21. The method of claim  20 , wherein said dermatological condition is selected from the group consisting of: 
       (i) conditions associated with keratinization, which optionally are associated with differentiation and/or proliferation;  
       (ii) keratinization disorders having an immunological and/or immunoallergic component;  
       (iii) dermal and epidermal proliferations, benign or malignant, which are of viral or non-viral origin;  
       (iv) bullosis or collagen disorders;  
       (v) chronological or UV-induced aging of the skin;  
       (vi) actinic keratoses and pigmentation;  
       (vii) stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids;  
       (viii) cutaneous atrophy;  
       (ix) cicatrization disorders;  
       (x) vibices;  
       (xi) promotion of cicatrization;  
       (xii) disorders of sebaceous function;  
       (xiii) general skin complaints of oral origin;  
       (xiv) immunological dermatological conditions; and  
       (xv) skin disorders associated with UV radiation exposure.  
     
     
       22. The method of claim  20 , wherein said disorder is selected from the group consisting of common acne, comedones, polymorphonuclear leukocytes, acne rosacea, nodulocystic acne, acne conglobata, senile acne, solar, medication-related acne, occupational acne, ichthyosis, ichthyosiform states, Darier's disease, palmoplantar keratoderma, leucoplasias and leucoplasiform states, cutaneous or mucous (buccal) lichen; psoriasis, cutaneous, mucous or ungual psoriasis, psoriatic rheumatism, eczema, respiratory atopy, gingival hypertrophy, common warts, flat warts, verruciform epidermodysplasia, oral or florid papillomatoses, proliferations induced by ultraviolet radiation, basocellular or spinocellular epithelioma; corneopathies, promyelocytic leukemia, arthritis, arteriosclerosis, and hypertension. 
     
     
       23. A pharmaceutical composition which comprises, in a pharmaceutically acceptable carrier, a pharmaceutically effective amount of carrier at least one compound according to claim  2 . 
     
     
       24. A composition according to claim  23 , wherein the concentration of said compound ranges from 0.001% and 5% by weight relative to the composition as a whole. 
     
     
       25. A cosmetic composition, which comprises, in a cosmetically acceptable carrier, at least one compounds according to claim  2 . 
     
     
       26. A composition according to claim  25 , wherein the concentration of said compound ranges from 0.001% and 3% by weight relative to the composition as a whole. 
     
     
       27. A method of hygiene comprising administering an effective amount of a cosmetic composition as defined in claim  25 , for body or hair hygiene. 
     
     
       28. The propynyl bioaromatic compound of formula I, in claim  1  wherein R 2  and R 3  are taken individually and are not both alkyl radicals. 
     
     
       29. The propynyl bioarmoatic compound of formual I, in claim  1 , wherein R 2  and R 3  together form with the adjacent aromatic ring a 5 or 6 membered ring optionally substituted with methyl groups and interrupted by a sulfur atom. 
     
     
       30. The propynyl bioaromatic compound of formula I which is selected from the group consisting of: 
       4-[3-(3,5-di-tert-betyl-4-oxo-2,5-cyclohexadien-1-ylidene)-1-propynyl]benzoic acid,  
       4-[3-(3,5-di-tert-betyl-4-hydroxyphenyl]-1-propynyl]benzoic acid,  
       2-hydroxy-4-[3-(3,5-di-tert-butyl-4-oxo -2,5-cyclohexadien-1-ylidene )-1-propynyl]benzoic acid, and  
       2-hydroxy-4-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-propynyl]benzoic acid.  
     
     
       31. The propynyl bioaromatic compound of formula I which the compound is 2-hydroxy-4-[3-(4,4-dimethylthiochroman-6-yl)-1-propynyl]benzoic acid.